Throughout this disclosure, various publications, patents and patent applications are referenced. The disclosures of these publications, patents and patent applications are herein incorporated by reference.
The present invention pertains to the treatment of mental or vascular disorders in patients.
It has been estimated that approximately 4% of the people in the world suffer from depression, which is not caused by any known underlying neurological disease. Depression affects people in all walks of society, from the very young to the very old. It often occurs without the presence of a precipitating event, and can be unresponsive to psychotherapy, environmental changes or to pharmacotherapy with the currently available medications.
When an individual is suffering from depression, he or she will usually be in a depressed mood, as well as experience a loss of interest or pleasure in all, or almost all, activities. These and associated symptoms last for a period of at least two weeks. The associated symptoms may include, but not be limited to, appetite disturbance, change in weight, sleep disturbance, psychomotor agitation or retardation, decreased energy, feelings of worthlessness or excessive or inappropriate guilt, difficulty thinking or concentrating, and recurrent thoughts of death or suicidal ideation or attempts. Further, a person suffering from depression can also experience fearfulness, anxiety, irritability, brooding or obsessive rumination, excessive concern with physical health, panic attacks, and phobias.
Of those having mental disorders, a correlation between allergic reactions, and particularly rhinitis, to mental disorders, including depression, has been reported. There has as yet, however, been no report of a physiological connection between allergies and mental disorders.
In fact, there does not appear be a direct physiological association between a depressive episode and allergic reactions. For example, while Bell et al. [Psychosom. Med. 52:517 (1990)] describe an interrelation between social anxiety, allergies and distressed affect, such as depression and anxiety, in some persons, the authors conclude that extreme shyness may only be a stable temperamental feature of a person who also has susceptibility to nasal allergies. Likewise, in a separate publication, Bell et al. [Psycother. Psychosom. 55:24 (1991)] report that affective manifestations lack a definitive relation to the duration or severity of allergic disorders.
Other publications reveal further complications in understanding the physiological relationship between allergies and mental disorders. It appears that the susceptibility to mental disorders can extend beyond the allergic sufferers themselves to their relatives. Kagan et al. [Psychosom. Med., 53:332 (1991)] describe temperament disorders in children suffering from hay fever. The authors report that first and second degree relatives of extremely shy children reveal a greater prevalence of hay fever and social anxiety.
Thus, while there are reports of a relationship between allergies and mental disorders, there is no definitive understanding of a physiological connection between these conditions. Without such an understanding, discovery of a method for alleviating mental disorders in those that suffer from them, or reducing the susceptibility of such individuals to mental disorder, can only be done empirically. On the other hand, there are methods for evaluating the fuctionality of a potential treatment for mental disorders.
Several lines of evidence suggest that an altered activity of brain serotonergic pathways is related to several neuropsychiatric disorders. For example, lower levels of 5-hydroxyindoleacetic (5-HIAA), the main metabolite of serotonin (5-HT) in the cerebrospinal fluid have been reported in clinical studies of aggression, depression, impulsive crime and alcoholism. Several important genes for normal brain serotonin function have been cloned, including tryptophan hydroxylase, the serotonin transporter, monoamine oxidases A and B and several serotonin receptors. In addition, serotonin receptor agonists and antagonists have been developed as drugs for treating specific neuropsychiatric disorders. Drugs with affinity for 5-HT2 receptors have been used to treat schizophrenia, Parkinsonism, and anxiety disorders. Several azapirones, such as buspirone, gepirone, and ipsapirone, have high affinities for 5HT1A receptors in the brain, and are used to treat anxiety. For example, clozapine which is an antipsychotic drug is used to treat schizophrenic patients who do not respond to other drug treatments. Clozapine has a strong affinity for the serotonin 5-HT2 subclass of receptors. In addition, 5-HT1A class agonists, such as buspirone, are effective treatments for anxiety. Highly selective 5-HT uptake inhibitors have been used successfully to treat depression.
Much recent interest in serotonin research has concentrated on the 5-HT7 receptor. This receptor and allelic variations of it are described in U.S. Pat. No. 5,763,183 as well as Shen et al, J Biol. Chem. 268:18200 and Roth et al, J Pharmacol. Exp. Ther. 268:1403.
This receptor is a guanine nucleotide regulatory protein coupled receptor (GPCR) and, on the basis of its sequence, it is thought to have the typical GPCR structure of seven hydrophobic transmembrane helices separated by three extracellular and three intracellular loops. The 5-HT7 receptor has a distinct pharmacological profile which includes high affinity for clozapine and related atypical antipsychotic agents as well as for some typical antipsychotic agents.
Pharmacological studies in humans have also suggested that abnormal function of 5-HT7 receptors might play a role in the etiology of certain mental/social disorders. These disorders include, but are not limited to, depression, alcoholism, weight management disorders (loss/obesity), social disorder, impotence/sexual dysfunction, panic, obsessive/compulsive disorder. 5-HT7 is also present in vascular tissue and can be associated with vascular-associated conditions. These conditions include, but are not limited to, migraines, stroke, orthostatic hypotension, gastrointestinal stasis, nausea, dizziness and jet lag.
Accordingly, a chemical that interacts with this receptor could be a valuable drug.
It is clear that what is needed is a method of treating an at risk population to lessen their risk of mental disorder and depression and vascular diseases. Also needed is a method to treat those that suffer from these disorders to reduce their symptoms of mental disorder.
The present invention provides methods for treatment of mental and vascular disorders. In one embodiment, the present invention provides a method of treating a patient suffering from mental or vascular disorder, comprising administering an effective amount of an anti-allergic medication to said patient under conditions such that the symptoms of said mental disorder are diminished.
In another embodiment, the present invention provides a method of treating a patient known to have suffered from a mental or vascular disorder, comprising administering an effective amount of an anti-allergic medication to said patient under conditions such that recurrence of the symptoms of said mental disorder are prevented or diminished.
The present invention is not limited to the type of mental disorder. Mental disorders include, but are not limited to, depression, alcoholism, weight management disorders (loss/obesity), social disorder, impotence/sexual dysfunction, panic, obsessive/compulsive disorder. Likewise, the present invention is not limited to the type of vascular disorders. Vascular disorders include, but are not limited to, migraines, stroke, orthostatic hypotension, gastrointestinal stasis, nausea, dizziness and jet lag.
The present invention is not limited to a type of patient having, or having experienced, a mental or vascular disorder. In one embodiment, the patient is susceptible to mental or vascular disorder. Alternatively, the patient may be suffering from a mental or vascular disorder, but not be of a group that is classified as susceptible to a mental or vascular disorder.
Likewise, the present invention is not limited to a specific anti-allergic medication. In one embodiment, the medication is an antihistamine. In a preferred embodiment, the antihistamine is a low-sedating or non-sedating antihistamine. In particularly preferred embodiments, the antihistamine is loratadine or a metabolite of loratadine (e.g., desloratadine).
When an antihistamine is used, it is preferably dosed in a range of 0.001 to 200 milligrams per kilogram. In a further preferred embodiment, the dosage is 0.01 to 100 milligrams per kilogram. In a particularly preferred embodiment, the dosage can be 1.0 to 60 milligrams per kilogram. Alternatively, the dosage is 0.001 to 200 milligrams per day, 0.01 to 100 milligrams per day or 1.0 to 60 milligrams per day.
All patents and literature references cited in this specification are hereby incorporated by reference in their entirety.
The present invention contemplates methods of treatment of mental disorders in patients having or being susceptible to a mental disorder. In one embodiment, the present invention contemplates administration of an effective amount of an anti-allergic medication, preferably in a pharmaceutically acceptable carrier or diluent. In another embodiment, a medication commonly used to treat mental disorder is administered in addition to the anti-allergic medication. Alternatively, more than one anti-allergic medication is administered as a combination medication to treat mental disorder. It should be understood that such combination medications can also be further combined with a medication commonly used to treat mental disorder. Such commonly used medications include, but are not limited to, benzodiazepines, monoamine oxidase inhibitors, tetracyclic antidepressants, selective serotonin reuptake inhibitors, tricyclic antidepressants, antipanic agents, antipsychotic agents, phenothiazines, psychostimulants and psychotropics.
As used herein, the term xe2x80x9cmental disorderxe2x80x9d refers to those provided in the Diagnostic and Statistical Manual (DSM IV), American Psychological Association (APA). These mental disorders include, but are not limited to affective disorders, neurotic disorders and unspecified depressive disorders. Examples of affective disorders include mood disorders, manic disorder, major depressive disorder and bipolar affective disorder. Mood disorders include, but are not limited to, depressive disorders, dysthymic disorder, bipolar disorders (I and II) and cyclothymic disorders. Likewise, examples of neurotic disorders include, but are not limited to, anxiety states, panic disorders, phobias, obsessive-compulsive disorder, post traumatic stress disorder, acute stress disorder, generalized anxiety disorder, attention deficit hyperactivity disorder, Tourette""s Syndrome and hysteria. Other conditions include sleep disorders, including breathing related sleep disorders.
The use of the term xe2x80x9cdepressionxe2x80x9d herein is intended to embrace clinical and subclinical forms of depression, particularly endogenous depression whose onset is or does not appear to be brought on by any particular event in the subject human""s life.
Thus, the term xe2x80x9cdepressionxe2x80x9d, as used herein includes those described in DSM IV, including, but not limited to, mood disorders, depression clinically diagnosed by professionals, such as psychiatrists, psychotherapists, psychologists, and therapists, as well as depression which may not be clinically diagnosed by a mental health practitioner but may nevertheless still be severe and prolonged. By way of non-limiting examples, clinically diagnosed depression includes dementia, acute depression, schizophrenia, and other clinical depression disorders, classified in DSM IV.
As used herein, the term xe2x80x9csusceptible to mental disorderxe2x80x9d and xe2x80x9csusceptible to depressionxe2x80x9d refers to individuals who are at risk for such disorders due to a predisposition to allergic response, such as reactions associated with histamine H1-receptor allergen interactions or abnormal activity associated with the 5-HT7 receptor or by being an immediate relative of someone who suffers such reactions or abnormal activities. Likewise, xe2x80x9csusceptible to a vascular disorderxe2x80x9d refers to individuals who are at risk for vascular disorders. For example, abnormal activity associated with the 5-HT7 receptor is one, but not the only, way to determine that an individual is susceptible to vascular disorder. Other methods are well known in the art.
As used herein, the term xe2x80x9callergic responsexe2x80x9d refers to an altered reactivity in response to an antigen and manifesting as various diseases, including, but not limited to, allergic rhinitis (seasonal or perennial, due to pollen or other allergens), asthma, polyps of the nasal cavity, unspecified nasal polyps, pharyngitis, nasopharyngitis, sinusitis, upper respiratory tract hypersensitivity reaction, and other allergies. Examples of allergies include, but are not limited to, allergic rhinitis (seasonal or perennial) or other respiratory allergy, food allergies and atopic skin reactions. Such responses can be Type I that are IgE-mediated immunologic reactions, or they can be Type II that are IgA, IgG or IgM mediated reactions.
As used herein, the term xe2x80x9canti-allergic medicationxe2x80x9d refers to a medication that controls an allergic response and the associated signs and symptoms of the manifested disease. Examples include, but are not limited to, antihistamines (e.g., histamine H1-receptor and histamine H3-receptor blocking agents), corticosteroids, nasally administered corticosteroids, orally administered corticosteroids, injected corticosteroids, cromones (e.g., cromolyn [Nasalcrom, Rhone-Poulenc Rorer, Collegeville, Pa.]), atopic corticosteroid creams. Examples of corticosteroidal anti-allergic medications include, but are not limited to, beclomethasone [Beconase AQ and Beconase Inhalation, Glaxo Wellcome, Research Triangle Park, N.C.], dexamethasone [Dexacort Phosphate in Turbinaire, Medeva, Fort Worth, Tex.], fluticasone [Flonase, Glaxo Wellcome, Research Triangle Park, N.C.], triamcinolone [Nasacort AQ and Nasacort, Rhone-Poulenc Rorer, Collegeville, Pa.], flunisolide [Nasalide and Nasarel, Roche, Nutley, N.J.], budesonide [Rhinocort, Astra], beclomethasone [Vancenase AQ, Schering, Madison, N.J.], and mometasone furoate [Nasonex, Schering, Madison, N.J.]. Examples of antihistamines include, but are not limited to, histamine H1-receptor blocking medication, histamine H3-receptor blocking medication, astemizole [Hismanal, Janssen, Titusville, N.J.], azatadine [Trinalin, Schering-Plough Corp., Madison, N.J.], cyproheptadine [Periactin, Merck, Rahway, N.J.], fexofenadine [Allegra, Hoechst Marion Roussel, Kansas City, Mo.], mizolastine, ebastine, loratadine [Claritin, Schering-Plough Corp., Madison, N.J.], desloratadine [also know as descarboethoxyloratadine, see U.S. Pat. Nos. 4,659,716; 5,595,997, and 5,731,319], phenindamine [Nolahist, Hoffinan-LaRoche, Nutley, N.J.], terfenadine [Seldane, Hoechst Marion Roussel, Kansas City, Mo.], diphenhydramine [Benadryl, Park Davis, Morris Plains, N.J.], bromodiphenhydramine [Bromo-Benadryl, Park Davis, Morris Plains, N.J.], carbinoxamine [Rondec, Dura, San Diego, Calif.], clemastine [Tavist, Sandoz, East Hanover, N.J.], dimenhydrinate [dimenhydrinate in Tubex, Wyeth Ayerst, Philadelphia, Pa.], diphenhydramine [Benadryl, Park Davis, Morris Plains, N.J.], diphenylpyraline, doxylamine [Unisom, Pfizer, New York, N.Y.], phenyltoloxamine [Kutrase, Schwarz, Milwaukee, Wis.], ephedrine [Quadrinale, Knoll, Mount Olive, N.J.], epinephrine, [Epipen, Center, Port Washington, N.Y.], pseudoephedrine, [Claritin-D, Schering, Madison, N.J.], acrivastine [Semprex D, Medeva, Fort Worth, Tex.], brompheniramine [Bromfed, Muro, Tewksbury, Mass.], chlorpheniramine [Children""s Tylenol Cold, McNeil, Fort Washington, Pa.], dexbrompheniramine, dexchlorpheniramine, dimethindene, pheniramine [Triaminc, Sandoz, East Hanover, N.J.], pyrrobutamine, triprolidine [Actifed, Warner Wellcome, Morris Plains, N.J.], methdilazine, promethazine [Phenergan, Wyeth-Ayerst, Philadelphia, Pa.], buclizine, cetirizine (Zyrtek, Pfizer, New York, N.Y.], chlorcyclizine [Mantadil, Glaxo Wellcome, Research Triangle Park, N.C.], cyclizine, hydroxyzine [Atarax, Pfizer, New York, N.Y.] and meclizine [Antivert, Pfizer, New York, N.Y.]. Such antihistamines can also be classified as sedating, low-sedating (e.g., cetirizine) or non-sedating (e.g., loratadine).
Dosing amounts and duration may vary according to the individual subject, the severity of the mental disorder or susceptibility to mental disorder and other factors which may affect the pharmaceutical kinetics of drug dosage and delivery. The influence of such factors on drug effectiveness is well-recognized in the art.
The compositions of the present invention may be administered in a number of pharmaceutically acceptable formulations including, for example, tablets and caplets. Preferably, the compositions are administered orally for ease of convenience.
Liquid formulations (oral or parenteral) are also contemplated. In addition, the compositions may take the form of suppositories, suitable for rectal administration. Those skilled in the art will appreciate that the forms of the compositions and amounts of the anti-allergic medication therein, may vary within pharmaceutically acceptable limits and still embrace the concept of this invention.
While the present invention is not limited to treatment in direct response to a mental disorder, in one embodiment the anti-allergic medication is administered in response to symptoms of a mental disorder. For example, a patient diagnosed with depression may be treated to relieve the symptoms of depression. Alternatively, a patient known to have suffered from a mental disorder may be given an anti-allergic medication to prevent a recurrence or to lessen the severity of the symptoms of a mental disorder, even though no symptoms are evident at the time of administration.
Likewise, the present invention is not limited to the type of patient suffering from or susceptible to a mental disorder. In one embodiment, the patient suffers from a mental disorder with no known physical disorder. On the other hand, the patient may suffer from a mental disorder and also be subject to allergic reactions, including allergic responses. For example, a patient subject to a mental disorder may also suffer periodic bouts of hay fever. In such a case, the present invention contemplates treatment of the mental disorder with an anti-allergic medication.
While not limited to any particular anti-allergic medications, the present invention contemplates administration of antihistamines to patients having symptoms of a mental disorder. In a preferred embodiment, the mental disorder is depression. Likewise, in such preferred embodiments, the antihistamines can be low-sedating or non-sedating antihistamines.